Based on an assembly of experimental observations in the rat, sheep, horse and human, the stress-responsive corticotropic-adrenal axis can be viewed as a dynamically adaptive feedback system supervised by key brain (hypothalamic) regulatory centers. The latter secrete episodic bursts of ACTH (adrenocorticotropic hormone)-releasing hormone (CRH) and arginine vasopressin (AVP). Hypophyseal-portal venous CRH and AVP signals act individually and jointly to stimulate ACTH synthesis, accumulation and secretion by the anterior pituitary gland. Systemic ACTH concentrations in turn drive adrenal cortisol secretion via a time-lagged feedforward dose-response function. Blood cortisol inhibits brain CRH/AVP production via both rapid rate-sensitive (differential) and time-delayed concentration dependent (integral) feedback mechanisms. Cortisol also represses corticotrope ACTH secretion via differential feedback and pituitary ACTH synthesis and storage via integral feedback control. While this connectionistic concept reasonably reflects available observations in the human and animal, precisely how the ensemble corticotropic axis maintains effectual homeostasis and reacts time-dependently to internal stress (disease) and external (environmental) demands is not known. To begin to formalize the key mechanisms that govern the time-evolving reactivity of this integrated network, the present goal is to: (a) frame and validate a new biomathematical formalism to encapsulate multivalent, nonlinear, time-lagged combined feedforward and feedback signaling; and (b) implement selected interventional experiments in the human and horse to further elucidate axis dynamics. To this end, we pose four specific aims: (1) to formalize a preliminary biomathematical construct that embodies the major physiological connections and dose-response interfaces within this life-supporting axis; (2) to test specific a priority clinical hypotheses of mechanisms linking 24-h (circadian) rhythmicity and ultradian (pulsatile) output; (3) to evaluate the mechanisms of homeostatic adaptation of CRH/AVP and ACTH release driven by acute cortisol withdrawal and repletion in the human and horse; and (4) to begin to estimate endogenous CRH/AVP-ACTH-cortisol dose-response properties in corresponding human and animal models. We believe that the foregoing unique marriage of clinical, experimental and biomathematical strategies will further enhance understanding of the complex and dynamic mechanisms underlying pathophysiological control of conjoint CRH/AVP-ACTH-cortisol secretion, and thus clarify new issues in the diagnosis, treatment and prevention of stress-related disease and disability.